Patients with thyroid cancer refractory to radioiodine (RAI) treatment are in need for novel treatment as their tumors are generally resistant to external radiation and conventional chemotherapy. To this date, no novel treatment has yet shown improved overall survival for these patients, despite improved progression-free survival in some patients treated with emerging targeted therapy regimen. We noted that several small molecular inhibitors in clinical trials are targeting signaling nodes we and others have shown to modulate thyroidal iodine accumulation. We, thus, hypothesize that small molecule Inhibitors in clinical trials targeting MEK, B f ^ F , Akt, PI3K or Hsp90, will also be effective in increasing/restoring thyroidal RAI accumulation. Two specific aims are proposed to test this hypothesis. Aim 1: Validate signaling nodes that increase thyroidal FiAl accumulation and identify mechanistic effectors of various inhibitors targeting these signaling nodes. We propose to: (a) Validate the effects of selected inhibitors in clinical trials on increasing RAI accumulation in cultured thyroid cells; (b) Determine whether inhibitor's efficacy on thyroidal RAI accumulation vary among cells predisposed with distinct genetic alterations; (c) Identify mechanistic effectors that underlie the increase of RAI accumulation by each inhibitor; and (d) Investigate possible convergence and dynamic interactions among these signaling nodes in modulating thyroidal RAI accumulation. Aim 2: Investigate the extent of increase and underiying determinants in thyroidal RAI uptake and retention per anatomic unit upon treatment of selected inhibitors at various tumor stages in thyroid cancer mouse models predisposed with distinct genetic alterations. Thyroidal RAI accumulation is contributed by the combination of RAI uptake and retention, two distinct processes that are mediated by distinct molecules. We propose to: (a) Quantify thyroidal RAI uptake and retention per anatomic unit in three thyroid cancer mouse models at various tumor stages; (b) Identify critical determinants of RAI uptake and retention in thyroid tumors predisposed with distinct genetic alterations; (c) Determine the extent of increase in RAI uptake and retention by selected inhibitors in thyroid tumors of aforementioned mouse models at various tumor stages, (d) Identify biomarkers and critical determinants that underlie the increase of thyroidal RAI uptake and retention by each inhibitor at various tumor stages of selected thyroid cancer mouse models. RELEVANCE (See instnjctions): Upon successful completion ofthe proposed studies, several inhibitors in clinical trials will not only serve as novel chemotherapeutic agents to halt tumor progression but will also allow remaining live tumor cells to be ablated by subsequent radioiodine therapy. Identifying critical mechanistic effectors of each inhibitor will allow us to develop biomarkers to predict and monitor responsiveness of corresponding inhibitor and/or develop alternative approaches to improve radioiodine therapy.